DE2212840A1 - Means for the treatment of cardiovascular disorders and pharmaceutical preparations for its use - Google Patents

Description

DR. MÜLLER-BORE DIPL.-PHYS. DR. MANlTZ DIPL.-CHEM. DR. DEUFEL

DIPL.-ING. FINSTERWALD DIPL-ING. G RAM KOW 9 O 1 9 fi A f)

PATENT LAWYERS

March 16, 1972

Dec 2 / th - P 2150

CMTEE EUHOPEM DE REGHERCHES MAUVEEUAY C.E.E.M. Eoute de Marsat, 63 Eiom France

Preparations for the treatment of cardiovascular disorders and pharmaceutical preparations for its use

Priority: France of March 16, 1971 No. 7109044

The invention relates to a new derivative of adenosine and its use as a remedy for the treatment of various cardiovascular disorders and affects, as well as those pharmaceutical preparations for the use of this medicinal product in human therapy.

The effect that AMP or adenosine - ^ '- monophosphoric acid, also called 5-A-aenjl acid, has on the blood cells, the enzymes, the isolated uterus, the isolated intestine, and the cerebral oxygen supply to the brain are already known from several publications Infarction or "in cerebral arteriosclerosis and on the contractility of strongly vascular muscles,

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like "for example of the heart.

On the other hand, the effects of papaverine on the same areas have already been described. It has been reported that in certain respects it is quite close to that of the AMP and / or such that it complements those or they compensated usable.

It is known that adenosine and the phosphonucleotides of adenine exert a vasodilatory effect on the coronary vessels and their application is intravenous.

It is also known that papaverine is the fixation of adenosine (nucleoside from which AMP arises through phosphorylation) inhibited by the blood cells, whereby it greatly increases its inhibitory effect on their agglutination. In this regard would the papaverine reduce the antitrombotic effects of the Boost adenosine. The same authors also report that papaverine prevents adenosine from penetrating the erythrocytes and its degradation by the adenosine diaminase inside inhibited. The coronary dilatatory effectiveness of papaverine would thus result from the circulating AMP Increase accumulation.

The papaverine lowers the oxidative phosphorylation on the Stage of the mitochondia. Every inhibitory effect of the oxidative phosphorylation is now transmitted through a crossover the metabolic processes. According to certain authors, this would reduce the pharmacological effects of papaverine at the heart level explain. It can be assumed that this inhibiting effect of papaverine is due to an activation of adenosine triphosphate transmits, combined with an acceleration

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the conversion of existing AMP into ATP with an increase the energy balance.

In any case, in these various biochemical and pharmacological works, each of these compounds, AMP and papaverine, own effects always considered separately been.

The known uses of AMP are practically those of adenine due to the fact that, like this, it is the coronary vasodilatation, causes bradycardia, hypotension and leukocytosis.

As for papaverine, a compound that is almost insoluble in water and therefore mainly in its form Hydrochloride is applied, it is used until now essentially as a spasmolytic to the contraction of the smooth Support muscle fibers.

Of the other currently known papaverine salts can one the hydrobromide, the hydroiodide, the methyl iodide, the Name acid sulfate, the acid oxalate, the succinate, the salicylate, the picrat and the picrolonate all of the same Such as hydrochloride and nitrite, which has been proposed against ringing in the ears, have therapeutic indications. The aforementioned salts, such as the hydrochloride, underwent a very rapid hydrolysis that made their injection painful and, since they are of poor solubility, they would be absorbed too slowly.

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The new cardiovascular remedy according to the invention is characterized in that it contains the adenosine ' Contains 5'-monophosphate 'of papaverine as a monohydrate.

In fact, it has been found according to the invention that adenosine-5'-monophosphoric acid (or 5'-adenylic acid or AMP) easily with the papaverine base with the formation of a new, acidic addition salt, a well-defined chemical structure, which is the adenosine 5'-monophosphate of papaverine, combined can be. Regardless of its own therapeutic effectiveness, this papaverine salt offers opposite the papaverine hydrochloride has the advantage of better water solubility and above all a very superior stability.

In the context of the invention it was also found that this new compound offers interesting pharmacological properties, which has made it a valuable remedy for treating disorders due to circulatory, brain, or peripheral disorders Coronary insufficiency and cardiovascular prevention.

The invention therefore also relates to the use of the new compound as a medicinal product and the pharmaceutical one Preparations for their use in human therapy.

It is of particular interest to note that the new, Medicines according to the invention to a much greater extent than a simple sum effect the beneficial properties each of the compounds, AMP and papaverine, from which it is created by combination, offers, while on the other hand it the shortcomings of these same connections, in particular

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it that of Papaverine, go off. For example, an increase in the turnover of the coronary arteries and the oxygen content of the venous blood of the coronary arteries, which is much "more significant than that of papaverine. On the other hand, it is heart-slowing, while papaverine is slightly tachycardial and it does less than increase the work of the heart It has also been found that the adenosine 5 ¹ monophosphate of papaverine has the advantage over AMP that it does not cause any, not even slight, myocardial depression.

The preparation of the preparation can generally be carried out as follows:

Approximately equimolar amounts of the adenosine-5'-monophosphoric acid monohydrate and the papaveri base are mixed, the mixture is then warmed gently "until the reaction is complete. This preparation is carried out", for example, as follows: To 3.65 pounds (0.01 mol) Adenosine 5'-monophosphoric acid monohydrate, suspended in a mixture of 4-5 ml of water and 5 ml of ethanol, 3.39 g (0.01 mol) of papaverine base (melting point = 147 ^° C.) are added. The mixture is warmed slightly to a final temperature of 40 G. The solution obtained is then filtered and the filtrate is concentrated under vacuum. The remaining product crystallizes rapidly. . Each drying at 50 ⁰ O until a constant weight is obtained $ 6.6 g of the desired product as the monohydrate, in l'orm of a crystalline white powder which melts at 140 C and is highly soluble in water.

The analysis of this compound of the gross formula C -, ^ H ^ _n - IL- 0 .. P, HpO void Moleimlargewicnt 704,64 gives the following results:

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G ° / b H ° / ο W / a

calculated: 51 , 13 5.29 11 , 92 found: 50 , 60 5.31 11 , 75

Pharmacodynamic properties:

The study of the pharmacodynamic properties of the Adenosine -5'-dionophosphate of papaverine was on the Performed on the basis of the following three experiments:

1. Arterial pressure in a chloral-anesthetized dog with the thorax closed;

2. Arterial pressure in the rat freed from both sides of the spinal cord and vagus;

3. Thigh throughput when anesthetized with chloral Dog.

For comparison purposes, each of these three experiments was carried out in the same way after using papaverine or AIiP alone, be it in equimolar doses or in doses of equal weight, carried out.

1. Arterial pressure in the anesthetized dog After chloral anesthesia by intravenous injection with a At a dose of 80 mg / kg, a carotid is isolated and catheterized she. Han connects the catheter to a mercury manometer. The continuous record of the arterial Printing is done cynographically. The table below gives

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the mean percentages of hypotonic potency and the mean duration of action.

mean dose percentage mean effect mean duration in minutes of hypotension

Adenosine 5'-mono- 4 mg / kg -65 % - 10 30 phosphate of papa.

verins

Papaverine 2 mg / kg -47 % - 6 5

ACP 2 mg / kg -27% ± 3 2

The effectiveness of the agent according to the invention has thus been proven the one or the other of the compounds used as starting compounds for its production, and who were considered from their most favorable point of view, consider. This superiority also lies in that Percentage of maximum effect and in the duration of effect; this indicates that the agent according to the invention is a particular one the periphery has an assisted vasodilatory effect.

2. Arterial pressure in the rat freed from spinal cord and vagus on both sides

After anesthesia with sodium 5-ethyl-5- (i-methylbutyl) barbiturate (Hembutal) when administered intraperitoneally at a dose of 34 mg / kg the spinal cord is destroyed by the method of Shipley and Suffering (see Proceedings of the Society for Exp., Biol. And Med. (1947), vol. 64). . ■

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Each of the three drugs tested is injected intravenously into the jugular vein, in a practically equimolar manner Dose to that of either of the other two.

The results, expressed as mean percentages of hypotonic potency and duration of action, are in the compiled in the following table:

Mean Dose Percentage - Mean We

mean of the duration of action ' ⁱⁿ minutes

Adenosine 5'-monophosphate

des Papaverine 4 mg / kg -46 % - ff 15

Papaverine 2 mg / kg -25 % - 6 years

AMP. 2 mg / kg -38 % - 9 5

This method makes the peripheral vasodilatory effectiveness of the agent according to the invention clearly evident. the end It can be seen from the table above that this effectiveness is always that of each of the starting substances used Products is superior and that, above all, the duration of action is much longer.

3. Throughput of the femoral vein in dogs After chloral anesthesia, each of the three aforementioned agents is applied intra-arterially, in a practically equimolar dose to that of each of the other two, ie: Adenosine 5 ¹ -monophosphate of papaverine: 1 mg / kg

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Papaverine: 0.5 mg / kg AMP: 0.5 mg / kg

The following table compares the effectiveness of the new agent with respect to papaverine and AI ¹ IP by arbitrarily assigning a therapeutic index (TI) of 100 to papaverine or AMP in one case and the other.

'DI = 100 (papaverine) to ¹¹ AMP ^{= 10} ° to planimetri-
value relative values: 1 147 - 25 to% increase to planimetri-
value % Increase 139-15 164-33 35 ^± 13

The same series of experiments is repeated, but with doses of 0.5 mg / kg of equal weight for each of the three agents while transferring the results according to the same arbitrary Hegel, one obtains:

Tl = 100 (papaverine) ¹¹ AMP *

relative values: to planimetri-
value To % increase to planimetri-
scherf to % increase 128.5-14 96 108-15 138.5 ± 17

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High here is the clear superiority of the 'effect of the agent according to the invention, regardless of whether it is in the value of the maximum effectiveness or in the planimetric value is.

Therapeutic indications:

The first clinical, undertaken with the means according to the invention Attempts justify its chief therapeutic Indications: Circulatory insufficiency with cerebral localization (cerebral infarction, arteriosclerosis), peripheral or coronary insufficiency; cardiovascular protection., The clinical Experiments were carried out with this compound using coated tablets at a dose of 100 mg of the active Principle carried out.

The uniform recipe is as follows:

Papaverine 100 mg adenosine 5-monophosphate

Grain starch i> 3

Cellulose, finely divided 37

Polyvinylpyrrolidone 2

Methyl cellulose ^l j

Stearic acid 1

Talk 2

The adenosine-5-monopLoEphat of Papaverine, the corn starch and the finely divided cellulose are mixed after previous sieving. Then wetted with a solution of polyvinylpyrrolidone and methylcellulose in alcohol at 96 ⁰ C. Well & a§- is on a sieve no. 32 APNEA granulated. It is dried at 40 ° in a drying cabinet. Stearic acid and talc are added, calibrated on a No. 31 AE'NOR sieve. Now it is tabletted and coated.

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The recommended daily doses based on the clinical trials are as follows:

oral. 0.5 "to 1.5 S.

parenteral. 50 mg Ms 5-00 mg rectal ■ 0.5 "to 1.5 g

• Preferred pharmaceutical forms:

The agent according to the invention is "preferably in the form of Solution for injection (intravenous), of gelatin capsules, of Tablets, drops or suppositories, using any pharmaceutically acceptable carrier or capsule material presented.

Administration:

The average recommended daily doses are as follows:

orally 250 mg to 1 g

parenteral (IV) '250 mg to 500 mg rectal 250 mg to 1 g

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Claims (2)

x patent claims Ή Adenosine 5 ¹ -raonophosphate honohydrate of papaverine. 2. Agents for treating cardiovascular disorders, thereby g e k e η η ζ e i c h η e t that it is the active substance Substance according to claim 1 in pharmaceutical compositions for u.ie Luiiiantlierapie in form of an injection solution, of gelacine capsules, tablets, drops, suppositories, in association with a pharmaceutically acceptable carrier or contains excipients in a therapeutically effective dose. . Gown according to claim 2 in a dosage useful for use in medical courts with regard to daily administration between about 250 mg and Λ g. 209841/1185 BATH ORIGINAL